Hepatic hepcidin/intestinal HIF-2α axis maintains iron absorption during iron deficiency and overload

J Clin Invest. 2019 Jan 2;129(1):336-348. doi: 10.1172/JCI122359. Epub 2018 Dec 10.

Abstract

Iron-related disorders are among the most prevalent diseases worldwide. Systemic iron homeostasis requires hepcidin, a liver-derived hormone that controls iron mobilization through its molecular target ferroportin (FPN), the only known mammalian iron exporter. This pathway is perturbed in diseases that cause iron overload. Additionally, intestinal HIF-2α is essential for the local absorptive response to systemic iron deficiency and iron overload. Our data demonstrate a hetero-tissue crosstalk mechanism, whereby hepatic hepcidin regulated intestinal HIF-2α in iron deficiency, anemia, and iron overload. We show that FPN controlled cell-autonomous iron efflux to stabilize and activate HIF-2α by regulating the activity of iron-dependent intestinal prolyl hydroxylase domain enzymes. Pharmacological blockade of HIF-2α using a clinically relevant and highly specific inhibitor successfully treated iron overload in a mouse model. These findings demonstrate a molecular link between hepatic hepcidin and intestinal HIF-2α that controls physiological iron uptake and drives iron hyperabsorption during iron overload.

Keywords: Gastroenterology; hypoxia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anemia, Iron-Deficiency* / genetics
  • Anemia, Iron-Deficiency* / metabolism
  • Anemia, Iron-Deficiency* / pathology
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Disease Models, Animal
  • HEK293 Cells
  • Hepcidins / genetics
  • Hepcidins / metabolism*
  • Humans
  • Intestinal Absorption*
  • Iron Overload* / genetics
  • Iron Overload* / metabolism
  • Iron Overload* / pathology
  • Iron* / deficiency
  • Iron* / metabolism
  • Liver / metabolism*
  • Liver / pathology
  • Mice
  • Mice, Transgenic

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Hamp protein, mouse
  • Hepcidins
  • endothelial PAS domain-containing protein 1
  • Iron